Devices and methods for reducing inflammation using electrical stimulation

ABSTRACT

Systems and methods for reducing pulmonary inflammation and/or increasing bronchial compliance in a patient utilize transcutaneous stimulation of neural structures in a region of an ear of a patient delivered by an auricular stimulation device having an in-ear component with a first electrode disposed in a patient&#39;s ear and an earpiece component with a second electrode placed around the auricle. A pulse generator may control delivery of therapy by delivering both a first series of stimulation pulses to the first electrode for stimulating a first neural structure(s) and a second series of stimulation pulses to the second electrode for stimulating second neural structure(s). The first and second electrodes are in non-piercing contact with tissue on and/or surrounding the ear. The systems and methods may be used to treat viral or bacteria infections, such as SARS, MERS, or COVID-19.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of, and claims priority toU.S. patent application Ser. No. 16/510,930 entitled “Device and Methodfor the Treatment of Substance Use Disorders,” filed Jul. 14, 2019 whichclaims priority to U.S. Provisional Patent Application Ser. No.62/777,569, entitled “Device and Method for the Treatment of SubstanceUse Disorders,” filed Dec. 10, 2018. All above identified applicationsare hereby incorporated by reference in their entireties.

BACKGROUND

According to the National Survey on Drug Use and Health, approximately2.1 million Americans are addicted to opioid pain relivers (OPRs), and513,000 are addicted to heroin. In 2017 there are a record 72,000overdose deaths, a rise of approximately 10% nationwide; largely fueledby new, synthetic opioids. The National Institutes of Health (NIH)reported that in the United States alone there are more than 115 deathsevery day related to opioids. Opioids produce a strong physiologicaldependence on its users; it is this dependence that makes it extremelydifficult, if not impossible, for user willing to stop consuming thistype of drug to do so without the intervention of a healthcareprofessional.

The physiological reaction caused by stopping opioid intake is known asOpioid Withdrawal. Opioid Withdrawal is generally extremely unpleasantand in some unattended cases may lead to death. The over usage ofopioids in the country has reach such levels that the government haslabeled the current situation as a national crisis. Interventions areneeded to help alleviate the Opioid Withdrawal symptoms felt byindividuals who are in the process of stopping opioid consumption.

Addressing strategies for addiction treatment and recovery has become amajor priority for government agencies given the substantial impact onhealth, social, and economic welfare. Treatment of opioid addictionincludes pharmacotherapies and psychosocial and behavioral adaptationapproaches including: residential treatment, mutual-help, and 12-Steptreatment programs. In many cases these interventions may beadministered alone or in combination with pharmacotherapy. Psychosocialopioid addiction treatment approaches show value and are an importanttreatment option. However, treatments with greater specificity,consistency, and patient compliance is needed.

SUMMARY OF ILLUSTRATIVE EMBODIMENTS

Currently, the United States is experiencing an opioid epidemic in theuse of prescription and non-prescription drugs that has continued torise since the 1990's. The need for safe and effective opioid withdrawaltreatment is demanding and largely unmet. According to the NationalSurvey on Drug Use and Health (NSDUH), approximately 2.1 millionAmericans are addicted to opioid pain relivers (OPRs), and 513,000 areaddicted to heroin. In 2005, there were an estimated 10 million chronicpain patients receiving daily, long-term treatment with OPRs. Thecontinuing increase in opioid consumption from 2005 to 2017 suggeststhat the number may now exceed 11 million.

A primary constraint on the overall percentage of treatment recipientsis the limited availability of licensed physicians that can prescribepharmacotherapies. Additionally, prescription opioids pose a variablelevel of risk on respiratory depression and abnormal cardiac activity,thus can only be obtained from licensed opioid treatment programs(OTPs). The lack of OTPs in many communities presents a major challengeto expanding access to methadone. In contrast, buprenorphine, a partialopioid agonist, has demonstrated a better safety profile compared tomethadone and can be prescribed in an office-based setting. However,buprenorphine includes federal limits on the number of patients aphysician may treat, ineligibility of nurse practitioners to prescribeit, and inadequate integration of buprenorphine into primary caretreatment.

Pharmacotherapies for opioid withdrawal include full-agonist treatmentwith methadone, partial-agonist with buprenorphine, and full-antagonistwith naltrexone. Methadone and buprenorphine are semi-synthetic opioidderivatives that bind to opioid receptors and allow addicted individualsto discontinue the misuse of opioids without experiencing withdrawalsymptoms. Buprenorphine can produce typical opioid effects and sideeffects such as euphoria and respiratory depression, however, itsmaximal effects are less than those of full agonists like methadone orheroin. Dose response curves specific to the agonist effects ofbuprenorphine increase linearly with higher doses of the drug until itreaches a plateau.

Buprenorphine can block the effects of full opioid agonists (i.e.methadone and heroin) and can precipitate withdrawal symptoms ifadministered to an opioid-addicted individual while a full agonist is inthe bloodstream. Buprenorphine has a higher affinity than other opioidsand as such will compete for the receptor and occupy that receptorblocking other opioids from binding. If there is an insufficient amountof buprenorphine to occupy and satisfy the receptors, withdrawalsymptoms can occur; in which case additional buprenorphine is givenuntil withdrawal symptoms disappear.

Lastly, naltrexone is an opioid-antagonist that competes foropioid-receptors and displaces opioid drugs from these receptors, thusreversing the effects of opioids. Naltrexone is capable of antagonizingall opioid receptors, but has a higher affinity to μ- rather than κ- andδ-receptors. By blocking the μ-opioid receptor, naltrexone acts todecrease the dopamine reward. The activity of naltrexone is thought tobe a result of both the parent and its 6β-naltrexol metabolite.Naltrexone's mechanism of action is similar to naloxone (opioidantagonist; found in Suboxone) except that it is longer acting.Naltrexone can be administered with a long-acting injection formulatedin microspheres that persists for 1 month after a single injection.

Due to inadequate and scarce treatment options, finding an effectivenon-pharmacological approach would be critical in improving andexpanding treatment for opioid withdrawal and addiction. Evidence existsfor the rapid and effective attenuation of signs and symptoms associatedwith opioid withdrawal through neurostimulation.

Percutaneous neurostimulation requires a percutaneous device which usessmall needles implanted into the skin to deliver neurostimulation.Percutaneous neurostimulation systems present numerous disadvantages andlimitations, which include: the location of the needles is critical andthus needle insertion must be performed by a trained professional heathprovider; the needles must be sterile; needle sterility requirementsequate to a minimal device shelf-life; movement or dislodged needlesrequires the attention of a trained clinic staff member; many patientshave inherent fear of needles; currently available systems cannot bere-used, re-charged, or used beyond its immediate battery life;currently available systems do not allow for fully customizablestimulation settings; currently available systems are not capable ofdetermining and reporting if stimulation is being delivered; currentlyavailable systems are not capable of gathering device compliance data;and currently available systems are not designed to be easy to use,aesthetically and cosmetically appealing which has an effect on patientcompliance.

Furthermore, patient compliance is one of the primary obstacles toclinical success, the proposed device has been designed to alert thetreating clinic staff when the device is not being used as prescribed,including device malfunction, and electrode misplacement. Since thenovel devices and therapy solutions described herein can be usedlong-term and can be easily applied by the user, the noveltherapy/device combination lends itself to be used for consumptionreduction, consumption secession, and long-term use avoidance.

In an aspect, the present disclosure relates to transcutaneousstimulation of auricular nerve fibers for the reduction of substanceconsumption, the reduction of symptoms associated with substancewithdrawal, and for the long-term maintenance to prevent substancerelapse. The proposed novel neuromodulation treatment does not requirepiercing the dermal layers and the required precision is such that anylayman can apply the device and receive therapy. In an aspect, thesystem is not required to be sterile, is easy to apply, and a user canapply without a clinician. The proposed treatment method along with thetreatment device overcomes all of the above-mentioned disadvantages.Given the large unmet medical need (i.e., opioid overuse), the fact thatthe treatment device proposed here has not been offered in the mannerhere proposed points to the non-obviousness nature of the proposedtreatment.

In some implementations, the treatment device can be used for treatingand/or managing symptoms for other indications. In some implementations,the treatment device can be used to provide therapy for the treatment ofneonatal abstinence syndrome by transcutaneous stimulation of auricularnerve fibers. Auricular acupuncture has recently been studied as anadjunctive therapy for neonatal abstinence syndrome in newborns.Non-insertive acupuncture (NIA) using traditional needles as shown in apublication by Filippelli, A. C. et. al. (2012). titled “Non-insertiveAcupuncture and Neonatal Abstinence Syndrome: A Case Series From anInner-city Safety Net Hospital. Global Advances in Health and Medicine,”published in Global Advances in Health and Medicine, 48-52. 2012, hereinincorporated by reference.

Evidence that the treatment device can be used to provide therapy forthe treatment of neonatal abstinence syndrome was provided in a studywhere a handheld laser was applied to the ear of newborns with neonatalabstinence syndrome resulting in some of the babies becoming morerelaxed during their course of treatment, as described in Raith, W., &Urlesberger, B. titled “Laser Acupuncture as An Adjuvant Therapy for aNeonate with Neonatal Abstinence Syndrome (NAS) Due to MaternalSubstitution Therapy: Additional Value of Acupuncture,” published inAcupuncture in Medicine, 2012, 32(6), 523-524 herein incorporated byreference. While more in-depth studies are needed to evaluateNon-insertive acupuncture as an effective adjunct therapy for neonatalabstinence syndrome in newborns, the early results show promise oftapping into the auricular neural pathways for treating neonatalabstinence syndrome.

Therapy systems and methods are provided for rapidly releasingendogenously produced opioid receptor agonists. The therapy system, insome implementations, includes a treatment device that allows theproposed therapy to be easily and reliably applied by almost anyone at arelatively low cost. Some advantages over the existing neuromodulationtreatment and related devices are: ease of use in both the applicationof the device, customizing therapeutic settings, and the actual wearingof the device, minimal risk of infection, users have the ability tosafely self-administer or restart the treatment without the need to goback to a clinic, significantly extended shelf life, reduced anxiety ofpatient due to non-invasiveness, long-term use option, customizabletherapeutic settings, ability to notify user, caregiver, and clinicianif therapy is interrupted or halted, ability to report overall usage toclinical staff or users for analysis, and the user does not have go backto the clinic to extend treatment or to use it at any given time whenthey feel it is needed present a major advantage over existingneuromodulation therapies, opening the door to a long-term maintenancetreatment.

In an aspect, the therapy device is configured to provide stimulationtherapy to release a different type and quantity of endogenous opioidpeptides based on varying stimulation parameters. Three families ofendogenous opioid peptides have been characterized in the CNS:enkephalins, endorphins, and dynorphins. Supporting animal data wasshown in a study examining effects of different stimulation frequencieson the type and quantity of endogenous opioid peptides released, asdescribed in a publication by Han, J. S., and Wang, Q. titled“Mobilization of specific neuropeptides by peripheral stimulation ofidentified frequencies,” in Physiology 1992, 7(4), 176-180, hereinincorporated by reference. Electro-acupuncture (EA) stimulation wasdelivered at two specific acupoints on the hindlimb. Rats were givenstimulation at 2, 15, and 100 Hz. Spinal perfusate was collected beforeand during stimulation. A clear difference in stimulation frequency andtype of opioid peptide release were shown including that 2 Hz waseffective at releasing enkephalins and beta-endorphins, and 100 Hz mosteffectively released dynorphin. No increase in opioid peptides wasobserved in non-responder rats that failed to show a response totail-flick during stimulation. Although, 15 Hz was capable of releasingenkephalin and dynorphin opioid peptides, another study shows thatalternating stimulation at 2 Hz/100 Hz maximized analgesic effects, thestudy by Han, J. S. titled “Acupuncture and endorphins,” published inNeuroscience letters, 2004, 361(1-3), 258-261 is herein incorporated byreference. The scientific evidence that pain-relief is achieved bydelivering neurostimulation to release endogenous opioid peptides andfill vacant opioid receptors, was later a tested hypothesis for reducingthe symptoms associated with opioid withdrawal.

In a randomized clinical trial, transcutaneous electrical acupointstimulation (TEAS) was delivered as an adjuvant to opioid detoxificationusing buprenorphine-naloxone, the clinical trial as reported by Meade,C. S., et al., titled “A randomized trial of transcutaneous electricacupoint stimulation as adjunctive treatment for opioid detoxification,Journal of Substance Abuse Treatment, 2010, 38(1), 12-21, is hereinincorporated by reference. Based on the preclinical evidence describedabove, TEAS was delivered at alternating low (2 Hz) and high (100 Hz)for 30 minutes each day for 3-4 days. In the active TEAS group, patientswere 77% less likely to have used any drugs as compared to 33% in shamtreatment at 2-weeks post-discharge. Additionally, active TEAS improvedpain perception and overall health.

In a preferred embodiment, a therapy system includes a treatment devicehaving an auricular component configured to be in contact with a patientand a pulse generator or controller configured to communicate with thetreatment device. In some implementations, a treatment device can beprovided as an assembled unit or as several pieces configured forconnection prior to use. In an example, the auricular component can beprovided in a sealed pouch and a pulse generator can be provided toconnect the auricular component to a connector on the pulse generator.In an aspect, the system is configured to have a removable stimulatorwithout the need to remove the auricular component and vice-versa. In anexample, the earpiece can be placed around the auricle of the patientbefore or after connection to the pulse generator.

In some implementations, the treatment device can be used to providetherapy including a first stimulation configured to stimulate pathwaysmodulating dynorphins release and a second stimulation configured tostimulate pathways modulating endorphins release. In someimplementations, the treatment device can be used to provide therapyincluding a first stimulation configured to stimulate pathwaysmodulating dynorphins release and a second stimulation configured tostimulate pathways modulating enkephalins release. In otherimplementations, the treatment device can be used to provide therapyincluding a first stimulation configured to stimulate pathwaysmodulating dynorphins release and a second stimulation configured tostimulate pathways modulating enkephalins and endorphins release.

In an example, the first stimulation can be a high frequency stimulationand the second stimulation can be a low frequency. In an example, thepathways modulating dynorphins release can include at least one of theauriculotemporal nerve, the lesser occipital nerve, and the greatauricular nerve. In an example, the pathways modulating dynorphinsrelease can include stimulation of dynorphin pathway via stimulation ofthe Parabrachial nucleus. In an example, the pathways modulatingendorphins and enkephalins release can include at least one of theauricular branches of the vagus nerve, the lesser occipital nerve, andthe great auricular nerve. In an example, the pathways modulatingendorphins and enkephalins release can include stimulation of endorphinsand enkephalins pathway via stimulation of the Arcuate nucleus of thehypothalamus.

To provide the therapy, a provider may adjust therapy parameters asneeded and start the therapy using the controls on either the pulsegenerator or the peripheral device. In some implementations, the therapyincludes providing two or more simultaneous and/or synchronizedstimulations. In an aspect, the therapy can involve applying a firststimulation having a first set of parameters at a first portion of thepatient's skin and applying a second stimulation having a second set ofparameters at a second portion of the patient's skin. When therapy isdone, the user may remove the earpiece and disconnect the earpiece fromthe pulse generator. In an example, the used earpiece can be replacedwith a new earpiece for the next session.

In some embodiments, treatment can be applied unilaterally (left orright) and yet in other embodiments a bilateral treatment may beapplied. In the case of a bilateral application two devices could beused; these two devices could be synchronized for yet a better systemicresponse. A single device with more channels or a single devicemultiplexing the outputs could also be used for a bilateral application.

The forgoing general description of the illustrative implementations andthe following detailed description thereof are merely exemplary aspectsof the teachings of this disclosure, and are not restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate one or more embodiments and,together with the description, explain these embodiments. Theaccompanying drawings have not necessarily been drawn to scale. Anyvalues dimensions illustrated in the accompanying graphs and figures arefor illustration purposes only and may or may not represent actual orpreferred values or dimensions. Where applicable, some or all featuresmay not be illustrated to assist in the description of underlyingfeatures. In the drawings:

FIG. 1A is a drawing identifying structures of an ear according to anexample;

FIG. 1B is a drawing of innervations of the ear amongst which are vagalrelated neural structures, auriculotemporal nerve structures, neuralstructures related to the lesser occipital nerve, and neural structuresrelated to the great auricular nerve;

FIGS. 1C-1G are drawings identifying neural structures and pathways formodulating the release of endogenous opiate receptor agonist, whichmodulate pain, as well as pathways modulating anti-inflammatory,pulmonary, and cognitive processes to an example;

FIG. 2A is a drawing of a treatment device including an auricularcomponent having an earpiece connected to a concha apparatus by a firstconnector, and a pulse generator connected to the earpiece of theauricular component by a second connector according to an example;

FIG. 2B is a drawing of an alternative view of the treatment deviceshown in FIG. 2A showing the concha apparatus including a firstelectrode or cymba electrode, and the earpiece including a secondelectrode and at least another electrode according to an example;

FIG. 2C is a drawing of a treatment device including a number ofelectrodes configured to be virtually grouped together to form one ormore effective electrodes according to an example;

FIG. 2D is a drawing of a side view of a portion of a treatment deviceincluding haptic feedback actuators between a pair of electrodesaccording to an example;

FIG. 2E is a drawing of an example treatment device having an earpiecewith a tragus appendix;

FIG. 3A is a drawing of an auricular component having an earpiece andconcha apparatus with shapes configured to aid in securing the treatmentdevice and respective electrodes to a respective ear structure accordingto an example;

FIG. 3B is an illustration of the auricular component worn on the ear ofa patient according to an example;

FIGS. 3C and 3D illustrate example auricular components including anelectrode for contacting the tissue of the tragus;

FIGS. 4A-4C are drawings of a concha apparatus having a shape configuredto aid in securing the concha apparatus and respective supportedelectrodes to a respective ear structure according to another example;

FIGS. 5A-5B are exploded views of components of the treatment deviceincluding a skin, a PCB layer, an adhesive layer composed of twoelements, a skin adhesive and a number of conductive adhesive elementsaccording to an example;

FIG. 6 is a drawing of a portion of an auricular component made from aflexible PCB according to an example;

FIG. 7A-7C are drawings of the flexible PCB encapsulated in a protectivecovering according to an example;

FIGS. 8A-8B are drawings of a structural-loaded component configured tofacilitate placement of the cymba electrode according to an example;

FIGS. 9A-9C are drawings of a compression-loaded component configured tofacilitate placement of the cymba electrode according to an example;

FIGS. 10A-10C are drawings of a system including the treatment device incommunication with third parties through a computing cloud and/or aperipheral device according to an example;

FIG. 11 is a drawing of a schematic of components of a pulse generatorin communication with components of the flexible PCB of the auricularcomponent according to an example;

FIG. 12 is a drawing of an electrode configuration and equivalentcircuit for providing therapy according to an example;

FIG. 13 is a drawing of a method for triggering multiple channels usinga single clock according to an example;

FIG. 14A is a flow chart of a method for providing therapy includingproviding a first stimulation at a first tissue location configured tostimulate a first pathway for modulating a first release of a firstendogenous peptide and a second stimulation at a second tissue locationconfigured to stimulate a second pathway for modulating a second releaseof a second endogenous peptide according to an example;

FIG. 14B are examples of target locations for stimulation of the firsttissue location;

FIG. 14C are examples of target locations for stimulation of the secondtissue location;

FIG. 14D is a flow chart of a method for providing therapy includingproviding a first stimulation at a first tissue location such thatneural activity at the arcuate nucleus of the hypothalamus (ARC) ismodulated such that it stimulates the Periaqueductal Gray Area (PAG) formodulating a first release of enkephalins and/or endorphins, and asecond stimulation at a second tissue location such that neural activityat the Parabrachial Nucleus (PbN) is modulated such that it alsostimulates the Periaqueductal Grey Area (PAG) for modulating a secondrelease of a dynorphins, according to an example;

FIG. 14E is a flow chart of an example method for providing therapy forincreasing bronchi compliance;

FIG. 14F is a flow chart of an example method for providing therapy fordecreasing pro-inflammatory processes; and

FIG. 15 is a bar graph showing data collected using the proposed systemaccording to an example.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The description set forth below in connection with the appended drawingsis intended to be a description of various, illustrative embodiments ofthe disclosed subject matter. Specific features and functionalities aredescribed in connection with each illustrative embodiment; however, itwill be apparent to those skilled in the art that the disclosedembodiments may be practiced without each of those specific features andfunctionalities.

Reference throughout the specification to “one embodiment” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with an embodiment is included inat least one embodiment of the subject matter disclosed. Thus, theappearance of the phrases “in one embodiment” or “in an embodiment” invarious places throughout the specification is not necessarily referringto the same embodiment. Further, the particular features, structures orcharacteristics may be combined in any suitable manner in one or moreembodiments. Further, it is intended that embodiments of the disclosedsubject matter cover modifications and variations thereof.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context expressly dictates otherwise. That is, unlessexpressly specified otherwise, as used herein the words “a,” “an,”“the,” and the like carry the meaning of “one or more.” Additionally, itis to be understood that terms such as “left,” “right,” “top,” “bottom,”“front,” “rear,” “side,” “height,” “length,” “width,” “upper,” “lower,”“interior,” “exterior,” “inner,” “outer,” and the like that may be usedherein merely describe points of reference and do not necessarily limitembodiments of the present disclosure to any particular orientation orconfiguration. Furthermore, terms such as “first,” “second,” “third,”etc., merely identify one of a number of portions, components, steps,operations, functions, and/or points of reference as disclosed herein,and likewise do not necessarily limit embodiments of the presentdisclosure to any particular configuration or orientation.

Furthermore, the terms “approximately,” “about,” “proximate,” “minorvariation,” and similar terms generally refer to ranges that include theidentified value within a margin of 20%, 10% or preferably 5% in certainembodiments, and any values therebetween.

All of the functionalities described in connection with one embodimentare intended to be applicable to the additional embodiments describedbelow except where expressly stated or where the feature or function isincompatible with the additional embodiments. For example, where a givenfeature or function is expressly described in connection with oneembodiment but not expressly mentioned in connection with an alternativeembodiment, it should be understood that the inventors intend that thatfeature or function may be deployed, utilized or implemented inconnection with the alternative embodiment unless the feature orfunction is incompatible with the alternative embodiment.

In some implementations, treatment systems, devices, and methods forstimulation of neural structures on and surrounding a patient's ear aredesigned for providing stimulation without piercing the dermal layers onor surrounding the ear. The stimulation, for example, may induceendogenous release of peptides, such as endorphins. Electrodes may befrictionally and/or adhesively retained against the skin on andsurrounding the patient's ear to target various nerve structures. Theelectrodes may have a substantial surface area in comparison to priorart systems relying upon dermal-piercing electrodes, such that multiplenerve terminals are stimulated by a single electrode during therapy. Forexample, a number of nerve terminals may be situated directly beneathand/or beneath and closely adjacent to the skin upon which the electrodeis positioned. By targeting multiple nerve terminals, in someembodiments, positioning of each electrode does not necessarily need tobe precise. Therefore, for example, a patient or caregiver may be ableto apply and remove the device as desired/needed (e.g., for sleeping,showering, etc.). Further, targeting multiple nerve terminals isadvantageous since stimulating multiple branches of a nerve elicits astronger response than stimulating a single branch, which is the casewhen using pinpoint electrodes such as needle electrodes.

The transdermal stimulation of these nerve regions enables a variety ofbeneficial treatments. In some examples, these include the treatment ofacute or chronic pain, inflammatory conditions, and cognitivedifficulties. FIGS. 1C-1E are drawings identifying neural structures andpathways for modulating the release of endogenous opioid receptoragonist, which modulates pain, as well as pathways modulatinginflammatory and cognitive processes. The Nucleus of the solitary tract(NTS) receives afferent connections from many areas including theTrigemino-cervical complex (TCC), the cervical vagus nerve as well asfrom the auricular branch of the vagus nerve (ABVN). The TCC is a regionin the cervical and brain stem area were trigeminal and occipital fiberssynapse, including the Auriculotemporal nerve, the lesser occipitalnerve and the greater auricular nerve. The TCC projects to multipleareas in the brain stem including, but not limited to the Nucleus RapheMagnus (NRM), the Locus Coeruleus (LC), Periaqueductal Gray (PAG),Nucleus Basalis (NBM), the Nucleus Ambiguus (NA), and Parabrachialnucleus (PbN). The NTS among others, also projects to the NRM, the LC,and the PAG as well as to high centers like the hypothalamus, includinginto the Arcuate Nucleus (ARC) which receives its majority ofnon-intrahypothalamic afferents from the NTS. Additionally, manyinterconnections exist amongst different brainstem nuclei (e.g., PAG,LC, NRM, NBM, PbN, PPN, NA); for example, the LC, PAG, and NRM projectto the NA.

These connections make this neural circuit extremely important formodulating pain, as production of endorphins, enkephalins, anddynorphins are modulated by this circuit. In addition, this neuralcircuits are crucial for learning and memory as well as for arousal andwakefulness. For example, an interaction between norepinephrine,produced by activity in the Locus Coeruleus (LC), Serotonin (5-HT),produced by activity in the Nucleus Raphe Magnus (NRM), andAcetylcholine (Ach) produced by activity in the Pedunculopontine Nucleus(PPN) or NBM is extremely important for memory and learning. Arousal andwakefulness is modulated, amongst others, by norepinephrine in thebrain.

There are descending indirect connections going to the heart, lungs,gut, and spleen. Indirect connections include connections where there isat least one synapse elsewhere before reaching the target. This meansthat modulating the activity of these neural circuits can affect therespective organs. In particular, heart rate can be modulated (e.g.,heart rate can be decreased and heart rate variability can beincreased); oxygen absorption can be increased at the lungs byincreasing the compliance of the bronchi tissue and thus increasing theoxygen transport availability therefore increasing the potential formore oxygen to be absorbed into the blood; gut motility can be increasedby descending pathways originating in the dorsal motor nucleus of thevagus nerve (DMV); since DMV activity is modulated by NTS activity,motility in the gut can be affected by modulating the activity in theNTS; and a decrease in circulating pro-inflammatory cytokines can beachieved by modulating spleen activity via NTS descending pathways.

Heart rate variability (HRV) is a reflection of the state of theautonomic nervous system (ANS). The sympathetic branch of the ANS, whichis more active during stress situations tends to increase heart rate(HR) and decrease HRV; the opposite is true for the parasympatheticbranch of the ANS, which tend to decrease HR and increase HRV. HigherHRV has been associated with morbidity and mortality in severalconditions as well as with well-being and has been used as a healthbiomarker.

There are at least three different opioid receptors, Mu (μ), Delta (δ),and Kappa (κ) in pain modulation. The body produces endogenous agonistpeptides for each of these three receptors. These peptides are calledendorphins, which primarily binds to the Mu (μ) receptors, Enkephalinwhich primarily binds to the Delta (δ) receptors, and Dynorphins, whichprimarily binds to the Kappa (κ) receptors. Pain studies suggest thatproduction of these endogenous peptides follow different pathways. Whileproduction of endorphins and enkephalin is mediated by activity in theArcuate Nucleus (ARC) in the hypothalamus, activity in the Parabrachialnucleus mediates production of dynorphins. Furthermore,electrostimulation experiment showed that dynorphin production was moreefficiently mediated by higher frequency than production of theendorphins and/or enkephalins; this suggests that while the dynorphinpathway is more efficiently activated by higher frequencies, theendorphins and enkephalins pathway is more efficiently activated bylower frequencies.

In some implementations, the treatment device can be used to induceneuronal plasticity or Neuroplasticity for provoking cognitiveimprovements, stroke recovery, PTSD, phobias, ADHD, ADD, dementiaincluding treating Alzheimer's disease. Neuroplasticity underlieslearning; therefore, strategies that enhance neuroplasticity duringtraining have the potential to greatly accelerate learning rates.Earlier studies have successfully demonstrated that invasive orimplanted vagus nerve stimulation (VNS) can drive robust, specificneural plasticity. Brief bursts of VNS are paired with training toengage pro-plasticity neuromodulatory circuits and reinforce thespecific neural networks that are involved in learning. This precisecontrol of neuroplasticity, coupled with the flexibility to be pairedwith virtually any training paradigm, establishes VNS as a potentialtargeted neuroplasticity training paradigm.

The vagus nerve is a cranial nerve that is located adjacent to thecarotid artery in the neck. Direct stimulation of the vagus nerveactivates the nucleus tractus solitarius (NTS), which has projections tonucleus basalis (NB) and locus coeruleus (LC). The NB and LC are deepbrain structures that release acetylcholine and norepinephrine, whichare pro-plasticity neurotransmitters important for learning and memory.Stimulation of the vagus nerve using a chronically implanted electrodecuff is safely used in humans to treat epilepsy and depression and hasshown success in clinical trials for tinnitus and motor impairmentsafter stroke. The auricular branch of the vagus nerve innervates thedermatome region of outer ear, being the region known as the cymbaconchae one of the areas innervated by it. Non-invasive stimulation ofthe left auricular branch of the vagus nerve may drive activity insimilar brain regions as invasive vagus nerve stimulation. Recentlyauricular neurostimulation has proven beneficial in treating a number ofhuman disorders.

In some implementations, the treatment device can be used to restoreautonomic balance such as cardiac heart failure, atrial fibrillation(AF), anxiety, stress, gastric motility, depression, cluster headaches,and migraines. Transcutaneous electrical stimulation of the tragus(e.g., the anterior protuberance of the outer ear), which is partlyenervated by the auricular branch of the Vagus nerve, can elicit evokedpotentials in the brainstem in human subjects. Based on theseobservations, it was demonstrated that atrial fibrillation inducibilitywas suppressed by transcutaneous low level-VNS stimulation, which wasachieved through stimulation of the auricular branch of the vagus nerveat the tragus in a canine. Noninvasive transcutaneous low level-VNSstimulation increases AF threshold (mitigates risk of AF), as well asalleviates AF burden in both canines and humans. In healthy subjects,transcutaneous low level-VNS stimulation can also increase heart ratevariability and reduce sympathetic outflow.

In some implementations, the treatment device is used to reduceinflammation caused by viral or bacterial infections. In the initialstages of infection, the body response includes the secretion ofpro-inflammatory cytokines. In some cases, controlling this inflammatoryresponse such that it can be reduced can help the body to heal faster.Inflammatory responses are a double-edged sword in the sense that it isnecessary to eradicate cells infected by viruses as well as bacteria.However, an excessive pro-inflammatory response can actually lead todeath. In particular in respiratory infections, pro-inflammatorycytokines may lead to an increase in pathogen replication. In addition,lung function may be compromised by the accumulation of pro-inflammatorycytokines. Studies suggest that the pro-inflammatory response in someindividuals (e.g., older people) is often excessive. In many of thesecases, it is this pro-inflammatory response that causes more harm thanthe infection itself resulting in the potential death of the infectedsubject. In response to Coronavirus Disease 2019 (COVID-19) and SevereAcute Respiratory Syndrome (SARS), for example, the human body producesan excessive pro-inflammatory response. In fact, evidence gathered sofar suggests that in some individuals with severe COVID-19 the bodyresponds by unleashing an exacerbated release of pro-inflammatorycytokines. Reducing the inflammatory response, e.g., through reducingcirculating pro inflammatory cytokines, will, in some cases, reduce thetime to heal and/or will reduce the time an infected person may need touse assistive respiratory therapy such as the need for a ventilator. Ingeneral, a patient stays on average less than 5 days on a ventilator;however, in the case of COVID-19, patients have been remaining onventilators for as much as 3 or 4 times longer; i.e., 15 to 20 days.Healthcare centers are generally equipped with enough ventilators toserve a population that will need them in average less than 5 days. Theincrease in the time a ventilator is needed in COVID-19 patients is afactor in the overall mortality rate seen in COVID-19 since manypatients in need of a ventilator will not have access to one. Viamodulation of NTS activity, treatment devices and methods describedherein can not only a) increase the compliance of the bronchi tissueultimately providing more oxygen to the body but also, b) decreaseinflammation in the lungs. For example, modulation of NTS activity candecrease the amount of circulating pro inflammatory cytokines. These twoeffects allow the novel treatment devices and methods described hereinto behave as an adjuvant therapy in the treatment of respiratoryinfections (e.g., Middle East respiratory syndrome coronavirus (MERS),severe acute respiratory syndrome (SARS), COVID-19, or chronicobstructive pulmonary disease (COPD)).

The compliance of the bronchi is produced via the modulation of theAutonomic Pulmonary Pathway, illustrated in FIG. 1F. In particular, thenovel treatment presented herein stimulates the ABVN and/or the ATNwhich have projections to the NTS. The NTS projects to LC, PAG and NRM.These brainstem nuclei deliver an inhibitory signal to airway-relatedpre-ganglionic neurons located in the nucleus ambiguus (NA). The NAsends a signal to the airway smooth muscle, via efferent pathways mainlythrough the vagus nerve, eliciting bronchodilation.

The anti-inflammatory effect is provided via activation of theAnti-inflammatory Pathway (a.k.a. the cholinergic anti-inflammatorypathway), as illustrated in FIG. 1G. In particular, the novel treatmentdescribed herein stimulates the ABVN and/or the ATN which, as statedbefore, have projections to the NTS; these projections elicitcholinergic anti-inflammatory effects via efferent pathways; mostly viathe vagus nerve. Systemic anti-inflammatory effects occur when the vagusnerve mediates spleen function, thereby reducing the amount ofcirculating pro-inflammatory cytokines. In addition, a localanti-inflammatory effect occurs at organs reached by the efferentpathways; for example at the lungs, gut, and heart.

To stimulate the various neural structures discussed above, in someimplementations, treatment devices may be designed for positioningagainst various surfaces on or surrounding a patient's ear. FIG. 1A is adrawing identifying structures of an ear showing amongst other theconcha cymba, the tragus, the antihelix, the helix, the externalauditory meatus, and the Lobule. FIG. 1B is a drawing of innervations ofthe ear amongst which are vagal related neural structures, for examplewithin the concha cymba, auriculotemporal nerve structures, for examplerostral to the auricle. In FIG. 1E, neural structures related to thelesser occipital nerve and neural structures related to the greatauricular nerve are shown, for example behind the auricle.

Turning to FIGS. 2A and 2B, a treatment device 200 is shown including anauricular component 201 having an earpiece 202 connected to a conchaapparatus 204 by a first connector 206, and a pulse generator 210connected to the earpiece 202 of the auricular component 201 by a secondconnector 214 according to an example. The first connector 206, in someembodiments, is releasably connected between the earpiece 202 and theconcha apparatus 204. For example, at least one of a proximal (earpiece202 side) end or at distal (concha apparatus 204 end) of the firstconnector 206 may be designed for releasable connection. In otherembodiments, the first connector 206 is integrated with the earpiece 202and concha apparatus 204, behaving as a conduit for bridging anelectrical connection between the earpiece 202 and the concha apparatus204. Similarly, in some embodiments, the second connector 214 isreleasably connected between the earpiece 202 and the pulse generator210. For example, at least one of a proximal (earpiece 202 side) end orat distal (pulse generator 210 end) of the second connector 214 may bedesigned for releasable connection. In other embodiments, the secondconnector 214 is integrated with the earpiece 202 pulse generator 210,behaving as a conduit for bridging an electrical connection between theearpiece 202 and the pulse generator 210. Either of the first connector206 or the second connector 214, in embodiments designed for releasableconnection, may include at least one of its proximal or distal endshaving a keyed connection with a corresponding port on the treatmentdevice 200 for snug (e.g., non-spinning) connection or for assuringelectrical alignment. In some embodiments designed for releasableconnection, either of the first connector 206 or the second connector214 is designed for locking connection. The locking connection, forexample, may be a water-resistant locking connection to protect againstshorting due to sweating, rain, etc.

In some embodiments, the earpiece 202 and/or the concha apparatus 204are designed from inexpensive materials, allowing the apparatus to bedisposable; lowering the cost per treatment and eliminating the need formaintenance. Disposable apparatus also provides for greater hygienics.

In some embodiments, the concha apparatus 204 includes a first electrode220 configured to be in proximity to vagal related neural structures toenable electrical stimulation of the vagal related neural structures,and the earpiece 202 includes a second electrode 222 configured to be inproximity to a neural structure related to the auriculotemporal nerve toenable electrical stimulation of the auriculotemporal nerve. Theearpiece 204 may further include at least another electrode 224, 226configured to be in proximity to neural structures related to the greatauricular nerve and/or its branches as well as the lesser occipitalnerve and/or its branches to enable electrical stimulation of thosestructures. In an example, the pulse generator 210 can include a returnelectrode 230 configured to provide a return path or reference toelectrodes 220-226. In another embodiment, electrodes 220-226 form pairssuch that for example electrodes 220 and 226 form a pair are used todeliver bipolar stimulation; in this example a second pair could beformed by electrodes 222 and 224 such that bipolar stimulation isprovided through them.

In yet another embodiment, electrodes 224 and 226 may be combined into asingle electrode and be used as a share pair for electrodes 220 and 222to produce biphasic pulses.

Turning to FIG. 2E, some embodiments further include at least one tragusappendix for contacting and stimulating the tragus. As illustrated inFIG. 2E, for example, a tragus appendix 284 containing a traguselectrode 282 configured for stimulating the tissue of the tragusextends from an earpiece 286 of a treatment device 280. In someembodiments, the tragus appendix 284 can be folded such that it is incontact with the exterior-facing tissue of the tragus and/or with theinterior-facing tissue of the tragus. For example, contacting the traguscan enable electrical stimulation of the auriculotemporal nerve and/orthe vagus nerve branch. The tragus electrode 282, for example, may beprovided instead of the first electrode 220 of the treatment device 200of FIGS. 2A and 2B and can be configured with electrode 226 as a pair.In another embodiment (not illustrated), the tragus electrode 282 may beprovided in addition to the first electrode 220, in which case both mayshare electrode 226 as their pair to produce biphasic pulses. In otherembodiment, another electrode (not shown), used as the pair forelectrode 282 to produce biphasic pulses, may placed, for example, belowelectrode 226.

In illustrative example, a treatment device such as the auricularcomponent 201 of FIGS. 2A and 2B may be donned as follows. Apply theearpiece 202 around the auricle of the patient, press against thepatient's skin such that exposed skin adhesives and adhesives/hydrogelsadhere to the skin. Next, place the concha apparatus 204 in the ear suchthat a first portion of the concha apparatus 204 sits outside theexternal ear canal in the cavum. Finally, flex or compress a second ordistal portion of the concha apparatus 204 supporting the cymbaelectrode until it goes into the cymba of the ear. In someimplementations, the earpiece 202 includes one or more protective linerson one or more of the skin adhesive, the cymba electrode, and thenon-cymba electrodes which are to be removed before use.

Turning to FIG. 2C, a treatment device can include a number ofelectrodes configured to be virtually grouped together to form one ormore effective electrodes according to an example. In an exemplaryembodiment, a treatment device can include a number of electrodes 208that can be grouped together to form into one or more effectiveelectrodes 240 a-c. In an example, a grouping of electrodes 240 a can beequivalent to electrode 222, a grouping of electrodes 240 b can beequivalent to electrode 224, and a grouping of electrodes 240 c can beequivalent to electrode 226.

Benefits of grouping smaller electrodes include having the ability tohave multiple electrodes each one with its own independently controlledcurrent source allows for the current to be steer providing betterspatial resolution and targeting capabilities. Electrodes can also bemade larger or combined such that for example in one embodimentelectrodes 1206 and 1208 be combined into one large contact. In anexample, the grouping of two or more electrodes (208, 224, 226) can bedone using a processor such as a field-programmable gate array (FPGA)such as FPGA 1112.

In a preferred embodiment, a treatment device includes an auricularcomponent 201 which has a number of electrodes that are configured to bein contact with the dermis in and around the outer ear. The auricularcomponent 201 includes at least one of the following electrodes: anelectrode configured to be in proximity to vagal related neuralstructures; for example at the cymba concha (also known as the concha ofthe cymba, concha cymba, and/or cymba) 204, an electrode 222 configuredto be in proximity to a neural structure related to the auriculotemporalnerve, an electrode configured to be in proximity to neural structuresrelated to the great auricular nerve and/or its branches, as well as thelesser occipital nerve and/or its branches, 224 and 226. Additionally,the treatment device includes a pulse generator or controller havingmanagement software for providing the user with at least one of:customizing the therapeutic output, receiving confirmation oftherapeutic delivery, and receiving and saving overall stimulation logs,diagnostics, and events.

In some implementations, a treatment device 250 can include one or morehaptic feedback actuators 270 between a pair of electrodes 228 accordingto an example (FIG. 2D). In an aspect, the one or more haptic feedbackactuators 270 can move 272 from a first position 270 to a secondposition 270′ in repetitive patterns. In an example, the repetitivepatterns can aid to mask sensations felt by stimulation of theelectrodes. In an aspect, the one or more haptic feedback actuators 270can be configured to isolate or electrically separate conductiveshunting pathways between electrodes 228, including between portions ofconductive gel 260.

In an aspect, an auricular component can include an earpiece and conchaapparatus having shapes configured to aid in securing the treatmentdevice and the electrodes to a respective ear structure. In an exemplaryembodiment, an auricular component 300 can include an earpiece andconcha apparatus having shapes 310, 320, 330 configured to aid insecuring the treatment device and the electrodes 220, 222, 224, 226 to arespective ear structure (See FIGS. 3A-3B). Shaped portions 310, 320,330, 332 of the earpiece and the concha apparatus are configured tointerface with structures of the ear (302, 304, 306, 308, 309) tofacilitate secure placement of the electrodes for providing therapy. Inanother exemplary embodiment, a concha apparatus 400 can have astructural shape configured to aid in securing the concha apparatus 400and allow for supported electrode(s) to maintain contact with arespective ear structure (See FIGS. 4A-4C). The concha apparatus 400includes a first member 402 connected at a distal elbow 406 to an arm404 having a second member 408 configured to fit within extrusions andnotches 410 a-b of the ear.

In some embodiments, an auricular component can include a tragus elementconfigured to extend over or wrap around the tragus of the ear. In anillustrative example, FIG. 3C illustrates an earpiece 340 including atragus extension 342. The tragus extension 342, for example, may beconfigured to contact an exterior-facing surface of the tragus. Inanother example, the tragus extension 342 may be foldable such that itcurves around a surface of the tragus. In this configuration, the tragusextension may have one or both of an interior surface facing electrodeand an exterior surface facing electrode. Turning to FIG. 3D, in anotherexample, an auricular component 350 includes an earpiece 352 including atragus bridging section 356 and a concha apparatus 354.

In some implementations, an earpiece assembly 500 includes a skin 502for overlaying a PCB layer 504 having electrodes 503 a-d (220, 222, 224,226, 228), an adhesive layer composed of two elements, a skin adhesive505 having corresponding apertures 506 to adhesive elements 508configured for enhancing electrical interfacing of the electrodes 503a-d with the skin (See FIGS. 5A-5B). In some embodiments, the adhesiveelements 508 can include a conductive hydrogel in another embodiment thehydrogel is infused with analgesic for a more comfortable stimulation.In an example, the hydrogel is on top of one or more contact surfaces onthe flex PCB. In an example, the skin 502 can be made from a flexiblepiece or material such as silicone.

In an example, a flexible PCB 602 can include electronic components tosuppress electrical spikes as well as a component to identify and/oruniquely identify the PCB (See FIG. 6). Exposed conductive surfaces 612,620, 622, 624 on the PCB 602 serve as contact point to connect thehydrogels 508 to the PCB 602. The PCB 602 extends forming a cable-likestructure 604 to integrate the cymba component 610 of the electrode 220in proximity to nerve branches related to vagal nerve structures 204without the need for soldering and/or connecting the electrode 220during assembly. In one embodiment, the cable-like structure forms ananchoring structure 606 which sits inside portions of the ear. In thisexample, PCB 602 connects to the pulse generator 210 via a slim keyedconnector 630. In another embodiment, more than one electrode can belocated on the cymba component 610. In this case, additional componentscan be added to the PCB 602 to accommodate additional electrodesincluding additional traces on the PCB 602. In an example, additionalconnections could extend along the cable-like structure 604 andconnector 630 can have additional contact pins. In another embodiment,an analog multiplexor could be added to control and/or direct orre-direct the stimulation pulses towards a desired electrode and/or setof electrodes.

In some embodiments, the circuit 602 on the earpiece assembly 500 isformed with printed electronics.

In an example, the flexible PCB can be encapsulated in a protectivecovering as shown in FIGS. 7A-7C. The protective covering can be madefrom a flexible material such as silicone. The protective covering canbe an encapsulation that may have different thickness and densities inorder to provide comfort to the touch and robustness and protection tothe PCB. The encapsulation is done with at least one material. In someembodiments, the encapsulation is done at least in using one mold and atleast one molding step.

In an aspect, a concha apparatus can include a component forfacilitating placement of the cymba electrode to portions of the ear.For example, the concha apparatus may be designed for frictionalengagement with a concha of the ear, thus retaining a position of theconcha apparatus external to the patient's ear canal in the concha. Inan exemplary embodiment, a concha apparatus can include astructural-loaded component 800 which facilitates frictional retentionof the cymba electrode 204 to portions of the ear (See FIG. 8A-8B).Compression loading, such as spring loading, has the added advantagethat it is self-fitting allowing a secure and comfortable fit fordifferent ear sizes. The presented shape (i.e., omega shape 814, 816)has the added advantage that it can be made with metal and non-metalmaterials. Other suitable shapes may be fabricated to allow astructural-loaded action using metal and/or non-metal materials or acombination of both metal and non-metal materials. The materials, forexample, may include shape retaining materials or shape memorymaterials. In this example, the cable-like structure 604 afterencapsulation with, for example, silicone 804 is routed such that thePCB 602 does not need to incorporate the anchoring structure 606. Inthis case, the cable-like structure 804 goes through a handle-likefeature 810 that can be utilized by the user to handle and placed thecomponent 800 on the user's ear.

An anchoring structure 812 is placed in the ear and the electrode inproximity to nerve branches related to vagal nerve structures 204 isplaced in the cymba. The use of an anchoring structure outside the earcanal instead of a part going into the ear canal for the placementserves three purposes, comfort, functionally (it does not block sound)and, safety (minimal risk of having a loose part going into the earcanal). Aside from the handle 810 and anchoring structure 812, component800 has two omega-like structures 814, 816 having a structural-loadedeffect, a flat structure 802 connecting structural-loaded components 814and 816 and a flat structure 818 attaching electrode 204 to component800. Structural-loaded structure 814 helps in directing the rest ofcomponent 800 (i.e. 802, 816, 818, 204) medially (i.e. towards theuser's head) while the structural-loaded structure 816 helps indirecting electrode 204 cranially inside the cymba crevice (i.e. towardsthe upper portion of the cymba crevice).

In an exemplary embodiment, a concha apparatus can include acompression-loaded component 900 which facilitates the placement of thecymba electrode 204 on the user's ear. (See FIG. 9A-9B). Compressionloading, such as spring loading has the added advantage that it isself-fitting allowing a secure and comfortable fit for different earsizes. The presented shape (i.e. classic spring) is usually fabricatedwith metallic materials. Other suitable shapes may be fabricated toallow a compression-loaded action using metallic materials, non-metalmaterials, or a combination of both metal and non-metal materials. Thematerials may include shape-retaining or shape-memory materials. In thisexample, the cable-like structure 604 after encapsulation with, forexample, silicone 904 is routed such that the PCB 602 does not need toincorporate the anchoring structure 606. In this case, the cable-likestructure 904 goes through holder 910 which can be utilized by the userto handle and placed the component 900 on the user's ear. An anchoringstructure 912 is placed in the ear and the electrode 204 in proximity tonerve branches related to vagal nerve structures is placed in the cymba.The use of an anchoring structure outside the ear canal instead of apart going into the ear canal for the placement serves three purposes,comfort, functionally (it does not block sound) and, safety (minimalrisk of having a loose part going into the ear canal). Aside from thehandle 910 and anchoring structure 912, component 900 has two springs914, 916, a flat structure 902 connecting the two springs 914 and 916and a flat structure 918 attaching electrode 204 to component 900.Spring 914 helps in directing the rest of component 900 (i.e., 902, 916,918, 204) medially (i.e., towards the user's head) while spring 916helps in directing electrode 204 cranially inside the cymba crevice(i.e. towards the upper portion of the cymba crevice). In someembodiments, a single wire 920 is shaped such that components 910, 912,914, 916, and 918 are formed (See FIG. 9C). In some embodiments, thewire is encapsulated into a comfortable-to-the-touch and flexiblematerial (e.g., silicone). In some embodiments, holder 910 is longer,for example it could bridge over the entire anchoring structure 912 fora more functional and comfortable handling.

In some implementations, the pulse generator 210 includes a battery,circuitry configured to produce therapy stimulation in communicationwith the electrodes of the auricular component 201. In some embodiments,the pulse generator includes at least one antenna configured to receiveprogramming instructions encoding stimulation parameters. In an aspect,the system is rechargeable to allow for long-term use.

In an exemplary embodiment, the auricular component 201 is connected toan electrical pulse generator 210 which produces the therapy stimulationgoing to the electrodes on the auricular component 201. In someimplementations, the pulse generator 210 is co-located in closeproximity with the auricle of the patient. For example, the pulsegenerator 210 may be designed into or releasably connected to a headapparatus similar an over the head or back of the head headphones bandor earmuffs band. In another example, the pulse generator 210 may bereleasably retained in a pocket of a cap or head wrap donned by apatient. In other embodiments, the pulse generator 210 is placed on thebody of the user, for example on the pectoral region just below theclavicle. In another embodiment, the pulse generator 210 can be clippedto the user's clothing or carried in the user's trousers pocket or in aspecially designed pouch. In further embodiments, the pulse generator isbuilt into the auricular component 201.

In some embodiments, the pulse generator 210 includes an input/output(I/O) interface for user control of the therapy. The I/O interface, forexample, may include a number of controls, such as buttons, dials, or atouch pad, for adjusting therapy. In some examples, the I/O interfacemay include one or more of a mode selection, a length of time selection,or a stimulation strength control. Separate controls, in a furtherexample, may be provided for the adjustment of the electrodes of theconcha apparatus and for the electrodes of the earpiece.

In some embodiments, the pulse generator 210 is remotely configurablevia wireless communication. In some embodiments, the wireless remotedevice may periodically request therapy status and in some embodimentsthe status, including any changes, may be communicated to a 3rd partysuch as a healthcare provider who is monitoring the therapy beingapplied to the user. For example, therapy provided via the pulsegenerator 210 may be controlled or adjusted at least in part using aperipheral device such as a mobile device, a tablet, or a personalcomputer. For example, a mode and/or stimulation strength may beadjusted by a clinical user (e.g., doctor, nurse, occupationaltherapist, etc.), while the timing (e.g., powering on and off and/orlength of time setting) of the stimulation may be user-controlled viathe I/O interface of the pulse generator 210. In another example, asoftware update to the pulse generator 210 may be delivered via wirelesscommunication. The wireless communication, in some examples, can includeradio frequency (RF) communication (e.g., Bluetooth) or near-fieldcommunication (NFC). The wireless communication may be enabled via anapplication installed on the peripheral device.

In some embodiments, other components of the treatment device areconfigurable by or capable of communication with a peripheral device.For example, data collected by the treatment device may be transferredto the peripheral device and thereby exchanged via a computing cloudwith third parties such as healthcare professionals and/or healthcareproviders

Turning to FIGS. 10A-10C, in some implementations, a treatment systemcan include a treatment device 1000 in communication with a network 1020and/or one or more peripheral devices 1010. Certain peripheral devices1010, further, may enable communication between the treatment device1000 and one or more third parties. Examples of peripheral devices 1010include a personal computer, a tablet, or phone. In some embodiments,the peripheral device(s) 1010 include a fitness-monitoring device, suchas a Fitbit, Apple Watch, or Garmin Smartwatch. In some embodiments, theperipheral device (s) 1010 include a health-monitoring device, such as aglucose meter, a holter monitor, an electrocardiogram (EKG) monitor, oran electroencephalogram (EEG) monitor. Further, the peripheral devices1010, in some embodiments, include a remote server, server farm, orcloud service accessible via the network 1020. Certain peripheraldevice(s) 1010 may communicate directly with the treatment device 1000using short-range wireless communications, such as a radio frequency(RF) (e.g., Bluetooth, Wi-Fi, Zigbee, etc.) or near-field communication(NFC). Certain peripheral device(s) 1010 may communicate with thetreatment device 1000 through another peripheral device 1010. Forexample, using Bluetooth communications, information from the treatmentdevice 1000 may be forwarded to a cloud service via the network 1020(e.g., using a Wi-Fi, Ethernet, or cellular connection). The network1020, in some examples, can include a local area network (LAN), widearea network (WAN), metro area network (MAN) or the Internet. In someembodiments, the network is a clinical LAN used for communicatinginformation in a medical environment, such as a hospital, in a secure(e.g., HIPAA-compliant) manner.

In an example illustrated in FIG. 10A, the treatment device 1000 isshown including an auricular component 1002 connected via a connector toa pulse generator 1004, and the pulse generator 1004 is wirelesslyconnected to the peripheral device(s) 1010 and/or the network 1020. Thisconfiguration, for example, may enable a patient, caregiver, or clinicaluser to adjust settings and/or monitor treatment controlled by the pulsegenerator 1004. For example, an application running on a peripheraldevice 1010 may provide one or more adjustable controls to the user foradjusting the delivery of therapy by the pulse generator 1004 to thepatient via the auricular component 1002. Further, feedback datagathered by the auricular component 1002 and/or the pulse generator1004, such as sensor feedback, may be supplied by the pulse generator1004 to one or more of the peripheral devices 1010. The feedback, forexample, may include sensor signals related to symptoms of the patientbeing treated by the treatment device 1000. A clinical user monitoringsensor metrics related to these signals may manually adjust the deliveryof therapy accordingly using the one or more adjustable controlsprovided by the application. Further, in some implementations, thefeedback may be used by one of the peripheral devices 1010 to generate anotification for review by the patient, a caregiver, or a clinician. Thenotification, for example, may include a low power notification, adevice removed notification, or a malfunction notification. In anillustrative example, the treatment device 1000 may monitor impedancemeasurements allowing closed-loop neurostimulation. The notificationsregarding removal or malfunction, for example, may be issued upondetermining that the impedance measurements are indicative of lack of aproper contact between one or more electrodes of the treatment device1000 and tissue on or surrounding the patient's ear. The notifications,for example, may be delivered to the patient and/or one or more thirdparties via an application executing on one of the peripheral devices1010. For example, the application may issue an audible alarm, present avisual notification, or generate a haptic output on the peripheraldevice 1010. Further, in some embodiments, the application may issue anotification via a communication means, such as sending an email, textmessage, or other electronic message to one or more authorized users,such as a patient, caregiver, and/or clinician.

Conversely, in some implementations, the configuration illustrated inFIG. 10A enables automatic adjustment of therapy delivery by reviewingfeedback provided by the treatment device and/or one or more peripheraldevices 1010 (e.g., fitness monitors and/or health monitors used by thepatient). In one example, a cloud platform accessible via the network1020 may receive the feedback, review present metrics, and relayinstructions to the pulse generator 1004 (e.g., via a Wi-Fi network orindirectly via a local portable device belonging to the patient such asa smart phone app in communication with the treatment device 1000). Thepulse generator, in a further example, may gather feedback from the oneor more fitness monitor and/or health monitor devices 1010, analyze thefeedback, and determine whether to adjust treatment accordingly.

Turning to FIG. 10B, in some implementations, the auricular component1002 of the treatment device 1000 may further be enabled for wirelesstransmission of information with one or more peripheral devices 1010.For example, the auricular component 1002 may include a short-rangeradio frequency transmitter for sharing sensor data, alerts, errorconditions, or other information with one or more peripheral devices1010. The data, for example, may be collected in a small non-transitory(e.g., non-volatile) memory region built into the auricular component1002.

In other implementations, the pulse generator 210 is included in theauricular component 1002 that is, they are co-located thus the need foran extension cable to connect them is not necessary. The auricularcomponent 1002 and pulse generator 210 may be wirelessly connected to anelectronic device (for example a personal computer, a tablet or a phone)1010 and/or to a remote server 1010 via the network 1020. In turn, insome embodiments, the electronic device 1010 is also wirelesslyconnected to a remote server via the network 1020.

As shown in FIG. 10C, different communication components of thetreatment device 1000 can be in communication with the peripheraldevice(s) 1010 or network 1020. In some implementations, the treatmentdevice 1000 includes at least one isolated port 1032 for wiredcommunication with the peripheral device 1010. The isolated port 1032,in some examples, may be a universal serial bus (USB) connection (e.g.,a mini-USB connection, a micro-USB connection, a USB-C port, etc.), anEthernet port, or a Serial ATA (SATA) connector. The isolated port 1032,for example, may be included in the pulse generator 1004 for updating asoftware version running on the pulse generator 1004 or forreprogramming treatment settings of the pulse generator 1004. Theisolated port(s) 1032 may be connected to a communications port engine1034 for enabling communications between a peripheral device 1010 andthe treatment device 1000 via the isolated port 1032. The communicationsport engine 1034 may couple the isolated port 1032 to one or moremicroprocessors 1036. For example, the communications port engine 1034may establish a direct (e.g., wired) communication link with one of theperipheral device(s) 1010 to transfer data 120 from a memory 1038 to theperipheral device 1010.

Further, a wireless radio frequency (RF) antenna (e.g., transmitter ortransmitter/receiver) 1040, in some implementations, is included in thetreatment device 1000. The RF antenna 1040 can be in wirelesscommunication with the peripheral device(s) 1010 directly or via thenetwork 1020. The RF antenna 1040, in combination with processingcircuitry for generating wireless communications (e.g., anothercommunication port engine 1034 or a portion of the microprocessor(s)1036) may function as a broadcast antenna, providing information to anyRF receiver in a receiving region of the treatment device 1000. Forexample, the RF antenna 1040 may broadcast sensor data, sensor metrics,alerts, alarms, or other operating information for receipt by one ormore peripheral devices 1010. In other implementations, the RF antenna1040, in combination with additional processing circuitry, may establisha wireless communication link with a particular peripheral device 1010.The wireless communication link, in some embodiments, is a securewireless communication link (e.g., HIPAA-compliant) for sharing patientdata with the peripheral device(s) 1010. The wireless communication linkmay be used to receive control settings from a peripheral device 1010for controlling the functionality of the pulse generator, for example.

Turning to FIG. 11, a schematic 1100 of components of a pulse generator1150 in communication with components of the flexible PCB 1160 of theauricular component is shown according to an example. The multichannelpulse generator circuit 1150 has at least one microcontroller or amicroprocessor 1110 with at least one core. When multiplemicrocontrollers or multiple cores are present, for example one controlsthe radio 1120 and other core(s) are dedicated to control the therapy.In one embodiment, a low power programmable logic circuitry (e.g., FPGAor PLD) 1112 is also available such that the microcontroller 1110 goesinto a low power mode as much as possible while the programmable logiccircuitry 1112 controls therapy delivery.

In some embodiments, an inverter circuit 1140 is used to generatebiphasic/bipolar pulses. In some embodiments, one inverter circuit isuse per channel, while in other embodiment, a single inverter is usedfor multiple channels. In one embodiment, each channel targets adifferent anatomical area 1148. A high voltage compliance (e.g., >50V,in other embodiments >70V, and yet in others >90V) may be used to ensurethere is enough margin on the electrical potential to generate currentdemanded by the intensity control 1142. In order to enhance safety, insome embodiments an over current detection circuit 1144 is present. Inone embodiment an impedance measuring circuit is present 1146, such thatimpedance can be tracked over time and to identify when the electrodesare not in contact or in good contact with the skin or if the cable isdisconnected, or if the electrodes have deteriorated or are defective.Monitoring impedance over time provides the added advantage that thecondition of the contact electrode can be followed; thus allowing thecircuit to alert the user when the contact electrodes are close to theirend of life or no longer viable.

In some embodiments, an isolated port 1118, such as a USB is used tocharge the battery, and to communicate with the microcontroller(s) 1110.The communication can be both ways, such that instructions or entire newcode can be uploaded to the microcontroller(s) 1110 and to downloadinformation stored in the memory 1122. In some embodiments, memory 1122can be added to the circuit as an external CHIP, while in otherembodiments, the memory 1122 can be internal to the microcontroller(s)1110. In some embodiments, the FPGA 1112 may also have internal memory.In some embodiments, an external trigger circuit 1124 is included, suchthat the stimulation can be started and/or stopped via an externalsignal. In some embodiments, the external trigger signal can be passedthrough the isolated port 1118; in yet other embodiments a modify USBconfiguration (i.e., not using the standard USB pin configuration) canbe used to pass the trigger signal. Using a modify USB configurationwill force a custom USB cable to be used thus ensuring that an externaltrigger cannot be done by mistake using an off-the-shelf USB cable.

In some embodiments, a hardware user interface is used to interact withthe circuit 1126. In an example, the user interface can comprise ofbuttons, LEDs, haptic (e.g., piezoelectric) devices such as buzzers,and/or a display, or a combination of any of them.

In some embodiments, an external master clock 1128 is used to drive themicrocontroller(s) 1110 and/or the FPGA 1112, in other embodiments theclock(s) can be internal or integrated or co-packaged with themicrocontroller(s) 1110 and/or the FPGA 1112. In some embodiments, oneor more oscillators, including in some cases adjustable oscillators 1114are used to set pulse parameters such as for example, frequency and/orpulse width.

In some embodiments, the auricular component 1160 is made from a thinflex PCB or printed electronics, such that it is light weight and can beeasily bent to accommodate different anatomies. In some embodiments, theauricular circuit 1160 has more than one channel. In one embodiment,each channel includes a peak suppressing circuit 1147 and electrodes1148 to contact the skin at the location of the target tissue. In someembodiments, the auricular circuit 1160 includes a unique chipidentifier or unique ID chip 1149. The unique ID chip can be used totrack usage as well as to prevent other no authorized circuits to beconnected to the multichannel pulse generator 1150. At least oneauricular circuit 1160 is connected to the multichannel pulse generator1150.

Turning to FIGS. 14A-14C, a method 1400 is disclosed for providingtherapy to a patient. The therapy, in some examples, may include thetreatment of acute or chronic pain, inflammatory conditions, and/orcognitive difficulties. In a particular example, the therapy may includethe treatment to abate withdrawal symptoms.

In some implementations, the method 1440 includes providing a firststimulation 1410 at a first tissue location configured to stimulate afirst pathway 1420 for modulating a first release 1430 of at least onefirst endogenous peptide. The first endogenous peptide release, forexample, may be an endorphin and/or enkephalins release Examples oftarget pathways and structures (1420) for stimulation of the firsttissue location include those modulating activity at/on the auricularbranch of the vagus nerve, the lesser occipital nerve, the greatauricular nerve, and the arcuate nucleus, for example as shown in FIG.14B. The first tissue location, for example, may be a tissue locationcontacted by one or more electrodes of the concha apparatus 204 of FIGS.2A-2C.

In some implementations, the method 1440 includes providing a secondstimulation 1440 at a second tissue location configured to stimulate asecond pathway 1450 for modulating a second release 1460 of a secondendogenous peptide. The second endogenous peptide release, for example,may be a dynorphin release. Examples of target pathways and structuresfor stimulation of the second tissue location include those modulatingactivity at/on the auriculotemporal nerve, the lesser occipital nerve,the great auricular nerve, and the parabrachial nucleus, for example asshown in FIG. 14C. In some examples, the first electrode 220 of FIG. 2B,an electrode in the second member 408 of FIG. 4A, the electrode 503 c ofFIG. 5B, an electrode disposed on the anchoring structure 606 of FIG. 6,or the electrode 1202 of FIG. 12 may be used to provide the firststimulation.

In some embodiments, providing the first stimulation (1410) andproviding the second stimulation (1440) involves providing a series ofsimultaneous and/or synchronized stimulation pulses to both the firsttissue location and the second tissue location. Each of the firststimulation (1410) and the second stimulation (1440) may be appliedusing the same or different parameters. The parameters, in someexamples, may include pulse frequency (e.g., low, mid-range, or high)and/or pulse width. Further, the parameters may indicate electrode pairsfor producing biphasic pulses. In a first illustrative example, thefirst stimulation may be applied using a low frequency, while the secondstimulation is applied using a mid-range frequency. Conversely, in asecond illustrative example, the first stimulation may be applied usinga mid-range frequency, while the second stimulation is applied using alow frequency. Other combinations of low, mid-range, and high frequencystimulations are possible depending upon the patient and the disorderbeing treated.

In other embodiments, the method 1400 includes automatically adjustingdelivery of the therapy (e.g., adjusting one or more parameters) basedon feedback received from the pulse generator or another computingdevice in communication with the pulse generator. The feedback, in someexamples, may include sensor feedback provided by the treatment deviceand/or one or more peripheral devices (e.g., fitness monitors and/orhealth monitors used by the patient, medical apparatus in a clinicalenvironment, etc.).

FIG. 14D shows a flow chart of an example method 1402 for providing atherapy as described in relation to FIG. 14A. In some implementations,the method 1402 includes providing the first stimulation 1410 such thatneural activity at the arcuate nucleus of the hypothalamus (ARC) ismodulated (1422) such that it stimulates the Periaqueductal Gray Area(PAG) (1470) for modulating a first release of enkephalins and/orendorphins (1480). In some implementations, the method 1402 includesproviding the second stimulation 1440 such that neural activity at theParabrachial Nucleus (PbN) (1452) is modulated such that it alsostimulates the Periaqueductal Grey Area (PAG) (1470) for modulating asecond release of a dynorphins (1482).

Turning to FIG. 14E, a flow chart of an example method 1401 isillustrated for providing therapy to increase bronchi compliance. Thetherapy of method 1401, for example, may encourage bronchodilation,thereby reducing airway resistance. Further, the therapy of method 1401may increase the oxygen transport availability of the lungs, increasingthe potential for more oxygen to be absorbed into the blood. The method1401, in some examples, may be applied in combatting COPD symptomsand/or symptoms produced by a viral or bacterial infection. The viralinfection, in some examples, can include SARS, MERS, or COVID-19. Themethod 1401, for example, may be performed at least in part by a pulsegenerator, such as the pulse generator 210 of FIGS. 2A and 2B, the pulsegenerator 1004 of FIG. 10A, or the pulse generator 1150 of FIG. 11.

In some implementations, the method 1401 begins with providing a firststimulation 1402 at a first tissue location configured to stimulate anautonomic pulmonary pathway 1406 for modulating bronchi compliance 1408.Examples of target pathways and structures for stimulation of the firsttissue location include those modulating activity at/on the auricularbranch of the vagus nerve, the lesser occipital nerve, the greatauricular nerve, and/or the nucleus ambiguus. The pathways, for example,may include a portion of the pathways illustrated in FIG. 1F. The firsttissue location, for example, may include a surface of an ear structurecontacted by an in-ear component of an auricular stimulation device. Insome examples, the first electrode 220 of FIG. 2B, an electrode in thesecond member 408 of FIG. 4A, the electrode 503 c of FIG. 5B, anelectrode disposed on the anchoring structure 606 of FIG. 6, or theelectrode 1202 of FIG. 12 may be used to provide the first stimulation.The first tissue location, in another example, may be a tissue locationcontacted by the tragus appendix 282 of FIG. 2E. In some embodiments,the first stimulation 1402 is supplied to multiple tissue locations. Forexample, the first stimulation 1402 may be applied to a first tissuelocation including a surface of an ear structure contacted by an in-earcomponent of an auricular stimulation device as well as to a secondtissue location on a tragus of the ear (e.g., contacted by the tragusappendix 282).

Modulating bronchi compliance 1408, in some implementations, includesmodulating activity at the NTS, thereby affecting activity at the LC,PAG, and/or NRM which in turn modulates activity in the NA such that thesmooth muscle tone in the airways is modified according to an example.

In some implementations, the method 1401 includes providing a secondstimulation 1404 at a second tissue location configured to stimulate theautonomic pulmonary pathway 1406 for modulating bronchi compliance 1408.Examples of target pathways and structures for stimulation of the secondtissue location include those modulating activity at and/or on theauriculotemporal nerve, the lesser occipital nerve, and/or the greatauricular nerve. The pathways, for example, may include a portion of thepathways illustrated in FIG. 1F. The second tissue location, forexample, may be a tissue location contacted by one or more of theelectrodes 222, 224, and/or 226 of the earpiece 202 of FIGS. 2A-2C.

In some embodiments, providing the first stimulation (1402) andproviding the second stimulation (1404) involves providing a series ofsimultaneous and/or synchronized stimulation pulses to both the firsttissue location and the second tissue location. Each of the firststimulation (1402) and the second stimulation (1404) may be appliedusing the same or different parameters. The parameters, in someexamples, may include pulse frequency (e.g., low, mid-range, or high)and/or pulse width. Further, the parameters may indicate electrode pairsfor producing biphasic pulses. In a first illustrative example, thefirst stimulation may be applied using a low frequency, while the secondstimulation is applied using a mid-range frequency. Conversely, in asecond illustrative example, the first stimulation may be applied usinga mid-range frequency, while the second stimulation is applied using alow frequency. Other combinations of low, mid-range, and high frequencystimulations are possible depending upon the patient and the disorderbeing treated.

In other embodiments, the method 1401 includes automatically adjustingdelivery of the therapy (e.g., adjusting one or more parameters) basedon feedback received from the pulse generator or another computingdevice in communication with the pulse generator. The feedback, in someexamples, may include a blood oxygen concentration, a breathing rate, abreathing variation, and/or tidal volume.

Turning to FIG. 14F, a flow chart of an example method 1490 isillustrated for providing therapy to decrease systemic pro-inflammatoryprocesses and/or pro-inflammatory processes in one or more targetorgans. The target organs, for example, may include the spleen, lungs,gut, and heart. The method 1490, in some examples, may be applied incombatting symptoms produced by COPD and/or produced by a viral orbacterial infection. The viral infection, in some examples, can includeSARS, MERS, or COVID-19. The method 1490, for example, may be performedat least in part by a pulse generator, such as the pulse generator 210of FIGS. 2A and 2B, the pulse generator 1004 of FIG. 10A, or the pulsegenerator 1150 of FIG. 11.

In some implementations, the method 1490 begins with providing a firststimulation 1492 at a first tissue location configured to stimulate ananti-inflammatory pathway 1496 for decreasing systemic pro-inflammatoryprocesses and/or pro-inflammatory processes in one or more target organs1498. The pathways, for example, may include a portion of the pathwaysillustrated in FIG. 1G. The first tissue location, for example, mayinclude a surface of an ear structure contacted by an in-ear componentof an auricular stimulation device. In some examples, the firstelectrode 220 of FIG. 2B, an electrode in the second member 408 of FIG.4A, the electrode 503 c of FIG. 5B, an electrode disposed on theanchoring structure 606 of FIG. 6, or the electrode 1202 of FIG. 12 maybe used to provide the first stimulation. The first tissue location, inanother example, may be a tissue location contacted by the tragusappendix 282 of FIG. 2E. In some embodiments, the first stimulation 1402is supplied to multiple tissue locations. For example, the firststimulation 1402 may be applied to a first tissue location including asurface of an ear structure contacted by an in-ear component of anauricular stimulation device as well as to a second tissue location on atragus of the ear (e.g., contacted by the tragus appendix 282).

Decreasing systemic pro-inflammatory processes and/or pro-inflammatoryprocesses in one or more target organs 1498, in some implementations,involves modulating at least a portion of the anti-inflammatory pathwayof FIG. 1G such that activity at the NTS is modulated affecting activityin efferent pathways through the celiac and parasympathetic ganglion,which in turn modulates activity in the spleen, lungs, gut, and/or heartsuch that an anti-inflammatory response is elicited.

In some implementations, the method 1490 includes providing a secondstimulation 1494 at a second tissue location configured to stimulate theanti-inflammatory pathway 1496 for decreasing systemic pro-inflammatoryprocesses and/or pro-inflammatory processes in one or more target organs1498. Examples of target pathways and structures for stimulation of thesecond tissue location include those modulating activity at and/or onthe auriculotemporal nerve, the lesser occipital nerve, and/or the greatauricular nerve. The pathways, for example, may include a portion of thepathways illustrated in FIG. 1G. The second tissue location, forexample, may be a tissue location contacted by one or more of theelectrodes 222, 224, and/or 226 of the earpiece 202 of FIGS. 2A-2C.

In some embodiments, providing the first stimulation (1492) andproviding the second stimulation (1494) involves providing a series ofsimultaneous and/or synchronized stimulation pulses to both the firsttissue location and the second tissue location. Each of the firststimulation (1492) and the second stimulation (1494) may be appliedusing the same or different parameters. The parameters, in someexamples, may include pulse frequency (e.g., low, mid-range, or high) orpulse width. Further, the parameters may indicate electrode pairs forproducing biphasic pulses. In a first illustrative example, the firststimulation may be applied using a low frequency, while the secondstimulation is applied using a mid-range frequency. Conversely, in asecond illustrative example, the first stimulation may be applied usinga mid-range frequency, while the second stimulation is applied using alow frequency. Other combinations of low, mid-range, and high frequencystimulations are possible depending upon the patient and the disorderbeing treated.

In other embodiments, the method 1490 includes automatically adjustingdelivery of the therapy (e.g., adjusting one or more parameters) basedon feedback received from the pulse generator or another computingdevice in communication with the pulse generator. The feedback, in someexamples, may include a blood oxygen concentration, a breathing rate, abreathing variation and/or tidal volume.

In further embodiments, combinations of the methods 1401 and 1490 may beused to increase bronchi compliance 1408 while also decreasing systemicpro-inflammatory processes and/or pro-inflammatory processes in one ormore target organs 1498. For example, the first stimulation 1402 of themethod 1401 may be delivered synchronously or simultaneously with thesecond stimulation 1492 of the method 1490 or vice-versa. In anotherexample, the therapy of the method 1401, including both the firststimulation 1402 and the second stimulation 1404 may be delivered for afirst period of time, and the therapy of the method 1490 including boththe first stimulation 1492 and the second stimulation 1494 may bedelivered for a second period of time. The combined methods may berepeated for a number of cycles of the first period of time and thesecond period of time. Based on feedback, the length of one or both ofthe first period of time and the second period of time may be adjusted,to both increase bronchi compliance 1408 and decrease systemicpro-inflammatory processes and/or pro-inflammatory processes in one ormore target organs 1498 in an efficient manner.

In an aspect, the stimulation targets specific neural targets in a localmanner using bipolar stimulation. In an aspect, the system can beprogrammed for optimal therapy according to the needs of individualusers including custom stimulation frequency, custom pulse width, customstim intensity (amplitude), independently controlled stimulationchannels. In some implementations, the treatment is configured to abatewithdrawal symptoms including acute and/or chronic pain. In an aspect,pain control is due to modulation of endorphin, enkephalins, and/ordynorphins output in opioid related systems. In an example, the therapycan be provided during surgery, and/or post-surgery to reduce dependencyof pain killer medications, including opioids, up to not needingmedication at all.

Turning to FIG. 12, an electrode configuration of an auricular component1200 and equivalent circuits 1210 a-b for providing therapy is shownaccording to an example. The auricular component 1200 is shown havingelectrodes 1202 (220), 1204 (222), 1206 (224), and 1208 (226) configuredto form corresponding circuits 1210 a-b according to an example. In anexample, equivalent circuit 1210 a is formed by electrode 1202 andelectrode 1206 which are configured to stimulate tissue portion 1220. Inthis example, tissue portion 1220 is configured to target the cymbaconchae region which is enervated by branches of the auricular branch ofthe vagus nerve and the region behind the ear which is enervated bybranches of the great auricular nerve and branches of the lesseroccipital nerve. In an example, equivalent circuit 1210 b is formed byelectrode 1204 and electrode 1208 which are configured to stimulatetissue portion 1222. In this example, tissue portion 1222 is configuredto target the region rostral to the ear which is enervated by theAuriculotemporal nerve as well as the region behind the ear which isenervated by branches of the great auricular nerve and branches of thelesser occipital nerve.

In an example, the tissue portion 1220 can be the concha which isstimulated at approximately 5 Hz. In an example, the tissue portion 1220can be the trigeminal nerve which is stimulated at approximately 100 Hz.

In an example, equivalent circuit 1210 a is stimulated by a firstchannel and equivalent circuit 1210 b is stimulated by a second channel.

FIG. 13 is a drawing of a timing diagram 1300 illustrating thetriggering multiple channels 1304, 1306 using a master clock 1302according to an example. In an exemplary embodiment, the clock 1302triggers pulses 1304 at a predetermined clock frequency. In an example,a first channel 1304 can be configured to trigger stimulation 1310 a-bof equivalent circuit 1210 a and a second channel 1306 can be configuredto trigger stimulation 1312 a-b of equivalent circuit 1210 b. In anexample, the triggering can be reversed where equivalent circuit 1210 bis triggered before equivalent circuit 1210 a.

In an example, stimulation 1310 a is configured to be triggered by everypulse of the master clock; i.e., at a 1-to-1 ratio. In an example,stimulation 1310 b is configured to be triggered following a specifictime interval after the pulse in stimulation 1310 a ends. In an example,stimulation 1312 b is configured to be triggered every two pulses of themaster clock; i.e., at a 2-to-1 ratio with the master clock. However,the triggering of stimulation 1312 b occurs after a specific time delayafter the master clock pulse 1314. In an example, stimulation 1312 a isconfigured to be triggered following a specific time interval after thepulse in stimulation 1312 b ends. In an example, stimulation 1310 a isoffset by stimulation 1312 a by a synchronous delay 1314. In an example,the synchronous delay 1314 is preferably 2 ms and can be as little aszero (making both channels to trigger simultaneously depending on themaster clock ratio for each channel) and as much as the master clockperiod less the combine duration of stimulation 1312 b and 1312 a plusthe time interval between them. In some embodiments this delay canamount to 10 ms.

In some implementations, the equivalent circuits are synchronized usinga master clock counter and a register per channel. By setting eachregister to a number of master clock pulses to trigger the respectivechannel, each channel is configured to be triggered when the channelregister value equals the master clock pulses. Subsequently, the counterfor each channel is reset after the channel is triggered. In an example,using a 6 bit counter and a 6 bit register, the trigger frequency can beas high as the master clock frequency (1:1) and as low as 1/64 of theclock frequency (64:1).

Stimulation delivery may vary based upon the therapy provided by thetreatment device. Frequency and/or pulse width parameters, for example,may be adjusted for one or more if not all electrodes deliveringstimulation. In some embodiments, frequency and/or pulse widthparameters are adjusted during therapy, for example responsive tofeedback received from monitoring the patient (e.g., using one or moresensors or other devices). The stimulation frequencies, in someexamples, may include a first or low frequency within a range of about 1to 30 Hz, a second or mid-range frequency within a range of about 30 to70 Hz, and/or a third or high frequency within a range of about 70 to150 Hz. Stimulation pulses, in some embodiments, are delivered inpatterns. Individual pulses in the pattern may vary in frequency and/orpulse width. Patterns may be repeated in stimulation cycles.

In one embodiment, the stimulation patterns are such that stimulatingfrequencies are not the same in all electrodes. In one embodiment, astimulation frequency is varied between 2 Hz and 100 Hz such thatdifferent endogenously produced opioid receptor agonist are released(e.g., Mu, Delta, Kappa, nociception opioid receptor agonist). In yetanother embodiment, the pulse width can be adjusted from between 20 and1000 microseconds to further allow therapy customization.

In some embodiments, different stimulation frequencies are used at thedifferent electrodes. In illustration, different combinations of high,mid-range and low frequencies can be used at either a cymba electrode(e.g., 204), an auriculotemporal electrode (e.g., 222), and/or a greatauricular nerve and lesser occipital nerve electrode (e.g., 224, 226).For example, a first or low frequency of between 1 to 30 Hz, or inparticular one or more of 1 to 5 Hz, 5 to 10 Hz, 10 to 15 Hz, 15 to 20Hz, 20 to 25 Hz, 25 to 30 Hz may be used at an in-ear electrode such asthe cymba electrode 204, while a second of high frequency of between 70and 150 Hz, or in particular one or more of 70 to 75 Hz, 75 to 80 Hz, 80to 85 Hz, 85 to 90 Hz, 90 to 95 Hz, 95 to 100 Hz, 100 to 105 Hz, 105 to110 Hz, 110 to 115 Hz, 115 to 120 Hz, 120 to 125 Hz, 125 to 130 Hz, 130to 135 Hz, 135 to 140 Hz, 140 to 145 Hz, 145 to 150 Hz is used at tissuesurrounding the ear, such as the auriculotemporal electrode 222. Inanother example, a third or mid-range frequency of between 30 to 70 Hz,or in particular one or more of 30 to 35 Hz, 35 to 40 Hz, 40 to 45 Hz,45 to 50 Hz, 50 to 55 Hz, or 55 to 60 Hz or 60 to 65 Hz or 65 to 70 Hzcan be used at one or more of the electrodes. In yet another example,one or more low or mid-range frequencies can be used at an in-earelectrode such as the cymba electrode 204, while one or more highfrequencies is used at an electrode contacting tissue surrounding theear, such as the auriculotemporal electrode 222. In other example, ahigh frequency can be use at an in-ear electrode such as the cymbaelectrode 204 while a low frequency can be used at an electrodecontacting tissue surrounding the ear, such as the auriculotemporalelectrode 222.

Different combination of pulse widths can be used at each electrode.Pulse widths, in some examples, may range from one or more of thefollowing: first or short pulse widths within a range of about 10 to 50microseconds, or more particularly between 10 to 20 microseconds, 20 to30 microseconds, 30 to 40 microseconds, 40 to 50 microseconds; second orlow mid-range pulse widths within a range of about 50 to 250microseconds, or more particularly between 50 to 70 microseconds, 70 to90 microseconds, 90 to 110 microseconds, 110 to 130 microseconds, 130 to150 microseconds, 150 to 170 microseconds, 170 to 190 microseconds, 190to 210 microseconds, 210 to 230 microseconds, or 230 to 250microseconds; third or high mid-range pulse widths within a range ofabout 250 to 550 microseconds, or more particularly between 250 to 270microseconds, 270 to 290 microseconds, 290 to 310 microseconds, 310 to330 microseconds, 330 to 350 microseconds, 350 to 370 microseconds, 370to 390 microseconds, 390 to 410 microseconds, 410 to 430 microseconds,430 to 450 microseconds, 450 to 470 microseconds, 470 to 490microseconds, 490 to 510 microseconds, 510 to 530 microseconds, or 530to 550 microseconds; and/or fourth or long pulse widths within a rangeof about 550 to 1000 microseconds, or more particularly between 550 to600 microseconds, 600 to 650 microseconds, 650 to 700 microseconds, 700to 750 microseconds, 750 to 800 microseconds, 800 to 850 microseconds,850 to 900 microseconds, 900 to 950 microseconds, or 950 to 1000microseconds. Different embodiments can use different ranges of pulsewidths at one or more of the electrodes (e.g., the electrodes 204, 222,224, 226, 230, 282).

In yet another embodiment, a variable frequency (i.e., stimulating anon-constant frequency) can be used at one or more of the electrodes(e.g., 204, 222, 224, 226, 230, 282). The variable frequency can be asweep, and/or a random/pseudo-random frequency variability around acentral frequency (e.g., 5 Hz+/−1.5 Hz, or 100 Hz+/−10 Hz).

In one embodiment, the auricular component (e.g., 201, 600) is made witha single flexible board and/or printed electronics containing electroniccomponents to uniquely identify it and, among other things, tocounteract any inductance produced by the connecting cable. Thisflexible electronic circuit is over-molded onto a skin 502 allowingopenings in it to allow direct contact with the back part of theskin-contacting electrodes 503. This auricular component 201, 600 islight-weight and extremely flexible allowing it to easily conform todifferent shapes presented by the anatomic variability of users. In oneembodiment, the molded auricular component is not homogenic, changingthe density and elasticity/flexibility at different places such that,for example, the part going around the ear is more flexible than thepart going on the ear.

In other embodiment, the flexible electronic circuit 600 is covered witha flexible material such as a closed cell foam.

In one embodiment, the skin-contacting electrodes can be made forexample of 3-layers, being the first layer a medical-grade double-sidedconducting adhesive tape, the second layer a conductive flexiblemetallic and/or fabric mesh for mechanical robustness and homogenicelectrical field distribution, and a third layer of self-adhesivehydrogel. A two-layer version is also possible in which both mechanicalrobustness and homogenic electrical field distribution is achieved bythe first layer, rendering unnecessary the second layer described in thethree-layer electrode.

In another embodiment, the PCB electrodes 503 are made such that theycover a similar surface area as the skin-contacting hydrogel electrodes;such that homogenic electrical field distribution is achieved at thehydrogels without the need of any additional conductive layer.

In an aspect, the system can record overall therapeutic delivery so thecaregiver/clinician can measure compliance. In one embodiment, themanagement software notifies the wearer, caregiver, clinician if thedevice has stopped delivering therapy. In an example, the managementsoftware can be configured to report data related to use, events, logs,errors, and device health status. In an aspect, the system can provideusage reports. In an aspect, the system can have a uniquely identifiableauricular component 201 that can be used in identifying users andreported data. In an example, the device health status can report on thecondition of the electrodes, the conductive hydrogel, and/or theanalgesic.

In an exemplary embodiment, the system utilizes feedback to monitorand/or modify the therapy. The feedback may be obtained from one or moresensors capable of monitoring one or more symptoms being treated by thetherapy. For example, upon reduction or removal of one or more symptoms,a therapeutic output may be similarly reduced or ceased. Conversely,upon increase or addition of one or more symptoms, the therapeuticoutput may be similarly activated or adjusted (increased, expanded upon,etc.). In some examples, the sensors may monitor one or more ofelectrodermal activity (e.g., sweating), movement activity (e.g.,tremors, physiologic movement), glucose level, neurological activity(e.g., via EEG), and/or cardio-pulmonary activity (e.g., EKG, heartrate, blood pressure (systolic, diastolic and mean)). Imaging techniquessuch as MRI and fMRI could be used to adjust the therapy in a clinicalsetting for a given user. In other embodiments, imaging of pupillarychanges (e.g., pupillary dilation) using, for example a common cellularphone and/or smart-glass glasses could be used to provide feedback tomake therapy adjustments. In some implementations, one or more sensorsare integrated into the earpiece and/or concha apparatus. One or moresensors, in some implementations, are integrated into the pulsegenerator. For example periodic monitoring may be achieved throughprompting the wearer to touch one or more electrodes on the system(e.g., electrodes built into a surface of the pulse generator) orotherwise interact with the pulse generator (e.g., hold the pulsegenerator extended away from the body to monitor tremors using a motiondetector in the pulse generator). In further implementations, one ormore sensor outputs may be obtained from external devices, such as afitness computer, smart watch, or wearable health monitor.

The monitoring used may be based, in part, on a treatment setting. Forexample, EEG monitoring is easier in a hospital setting, while heartrate monitoring may be achieved by a sensor such as a pulsometer builtinto the earpiece or another sensor built into a low budget healthmonitoring device such as a fitness monitoring device or smart watch.

In an illustrative example, feedback related to electrodermal activitycould be used to monitor and detect a speed or timing of a symptomand/or therapeutic outcome. In an example, the electrodermal activitycould be sensed by electrodes on the auricular component 201. In anotherexample, the electrodermal activity could be detected by electrodes onanother portion of the body and communicated to the system.

In some implementations, the system can further include one or moremotion detectors, such as accelerometers or gyroscopes, that can be usedgather information to modulate the therapy. In an example, the one ormore motion detectors are configured to detect a tremor and/orphysiologic movement. In an aspect, the tremor and/or the physiologicmovement can be indicative of at least one of the underlying conditionand the treatment to the underlying condition. In an example, the tremorand/or physiologic movement can be indicative of symptoms associatedwith substance withdrawal. In an aspect, feedback from glucosemonitoring can be used to modulate the therapy.

In yet other implementations, EKG can be used to assess heart rate andheart rate variability, to determine the activity of the autonomicnervous system in general and/or the relative activity of thesympathetic and parasympathetic branches of the autonomic nervoussystem, and to modulate the therapy. Autonomic nervous activity can beindicative of symptoms associated with substance withdrawal. In anaspect, the treatment device can be used to provide therapy for treatingcardiac conditions such as atrial fibrillation and heart failure. In anexample, therapy can be provided for modulation of the autonomic nervoussystem. In some implementations, the treatment device can be used toprovide therapy to balance a ratio between any combinations of theautonomic nervous system, the parasympathetic nervous system, and thesympathetic nervous system.

In an aspect, the system can monitor impedance measurements allowingclosed-loop neurostimulation. In an example, monitoring feedback can beused to alert patient/caregiver if therapy is not being adequatelydelivered and if the treatment device is removed.

Turning to FIG. 15, a graph 1500 is shown of data collected using theproposed system according to an example. Clinical Opiate WithdrawalScore (COWS) over time was collected from two subjects 1502 a, 1502 bbeing treated with the proposed therapy. Therapy included using Lowfrequency (5 Hz) between the cymba electrode 204 and an electrode 224,and High frequency (100 Hz) between the auriculotemporal electrode 222and electrode 226. As illustrated, the COWS score dramatically decreasedover time 1504, in particular within the first 30-60 minutes.

Reference has been made to illustrations representing methods andsystems according to implementations of this disclosure. Aspects thereofmay be implemented by computer program instructions. These computerprogram instructions may be provided to a processor of a general purposecomputer, special purpose computer, or other programmable dataprocessing apparatus to produce a machine, such that the instructions,which execute via the processor of the computer or other programmabledata processing apparatus, create means for implementing thefunctions/operations specified in the illustrations.

One or more processors can be utilized to implement various functionsand/or algorithms described herein. Additionally, any functions and/oralgorithms described herein can be performed upon one or more virtualprocessors, for example on one or more physical computing systems suchas a computer farm or a cloud drive.

Aspects of the present disclosure may be implemented by hardware logic(where hardware logic naturally also includes any necessary signalwiring, memory elements and such), with such hardware logic able tooperate without active software involvement beyond initial systemconfiguration and any subsequent system reconfigurations. The hardwarelogic may be synthesized on a reprogrammable computing chip such as afield programmable gate array (FPGA), programmable logic device (PLD),or other reconfigurable logic device. In addition, the hardware logicmay be hard coded onto a custom microchip, such as anapplication-specific integrated circuit (ASIC). In other embodiments,software, stored as instructions to a non-transitory computer-readablemedium such as a memory device, on-chip integrated memory unit, or othernon-transitory computer-readable storage, may be used to perform atleast portions of the herein described functionality.

Various aspects of the embodiments disclosed herein are performed on oneor more computing devices, such as a laptop computer, tablet computer,mobile phone or other handheld computing device, or one or more servers.Such computing devices include processing circuitry embodied in one ormore processors or logic chips, such as a central processing unit (CPU),graphics processing unit (GPU), field programmable gate array (FPGA),application-specific integrated circuit (ASIC), or programmable logicdevice (PLD). Further, the processing circuitry may be implemented asmultiple processors cooperatively working in concert (e.g., in parallel)to perform the instructions of the inventive processes described above

The process data and instructions used to perform various methods andalgorithms derived herein may be stored in non-transitory (i.e.,non-volatile) computer-readable medium or memory. The claimedadvancements are not limited by the form of the computer-readable mediaon which the instructions of the inventive processes are stored. Forexample, the instructions may be stored on CDs, DVDs, in FLASH memory,RAM, ROM, PROM, EPROM, EEPROM, hard disk or any other informationprocessing device with which the computing device communicates, such asa server or computer. The processing circuitry and stored instructionsmay enable the pulse generator 210 of FIGS. 2A-2C, the pulse generator1004 of FIGS. 10A-10C, or the pulse generator 1150 of FIG. 11 to performvarious methods and algorithms described above. Further, the processingcircuitry and stored instructions may enable the peripheral device(s)1010 of FIGS. 10A-10C to perform various methods and algorithmsdescribed above.

These computer program instructions can direct a computing device orother programmable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablemedium produce an article of manufacture including instruction meanswhich implement the function/operation specified in the illustratedprocess flows.

Embodiments of the present description rely on network communications.As can be appreciated, the network can be a public network, such as theInternet, or a private network such as a local area network (LAN) orwide area network (WAN) network, or any combination thereof and can alsoinclude PSTN or ISDN sub-networks. The network can also be wired, suchas an Ethernet network, and/or can be wireless such as a cellularnetwork including EDGE, 3G, 4G, and 5G wireless cellular systems. Thewireless network can also include Wi-Fi, Bluetooth, Zigbee, or anotherwireless form of communication. The network, for example, may be thenetwork 1020 as described in relation to FIGS. 10A-10C.

The computing device, such as the peripheral device(s) 1010 of FIG.10A-10C, in some embodiments, further includes a display controller forinterfacing with a display, such as a built-in display or LCD monitor. Ageneral purpose I/O interface of the computing device may interface witha keyboard, a hand-manipulated movement tracked I/O device (e.g., mouse,virtual reality glove, trackball, joystick, etc.), and/or touch screenpanel or touch pad on or separate from the display.

A sound controller, in some embodiments, is also provided in thecomputing device, such as the peripheral device(s) 1010 of FIG. 10A-10C,to interface with speakers/microphone thereby providing audio input andoutput.

Moreover, the present disclosure is not limited to the specific circuitelements described herein, nor is the present disclosure limited to thespecific sizing and classification of these elements. For example, theskilled artisan will appreciate that the circuitry described herein maybe adapted based on changes on battery sizing and chemistry or based onthe requirements of the intended back-up load to be powered.

Certain functions and features described herein may also be executed byvarious distributed components of a system. For example, one or moreprocessors may execute these system functions, where the processors aredistributed across multiple components communicating in a network suchas the network 1020 of FIGS. 10A-10C. The distributed components mayinclude one or more client and server machines, which may shareprocessing, in addition to various human interface and communicationdevices (e.g., display monitors, smart phones, tablets, personal digitalassistants (PDAs)). The network may be a private network, such as a LANor WAN, or may be a public network, such as the Internet. Input to thesystem may be received via direct user input and received remotelyeither in real-time or as a batch process.

Although provided for context, in other implementations, methods andlogic flows described herein may be performed on modules or hardware notidentical to those described. Accordingly, other implementations arewithin the scope that may be claimed.

In some implementations, a cloud computing environment, such as GoogleCloud Platform™, may be used perform at least portions of methods oralgorithms detailed above. The processes associated with the methodsdescribed herein can be executed on a computation processor of a datacenter. The data center, for example, can also include an applicationprocessor that can be used as the interface with the systems describedherein to receive data and output corresponding information. The cloudcomputing environment may also include one or more databases or otherdata storage, such as cloud storage and a query database. In someimplementations, the cloud storage database, such as the Google CloudStorage, may store processed and unprocessed data supplied by systemsdescribed herein.

The systems described herein may communicate with the cloud computingenvironment through a secure gateway. In some implementations, thesecure gateway includes a database querying interface, such as theGoogle BigQuery platform.

While certain embodiments have been described, these embodiments havebeen presented by way of example only, and are not intended to limit thescope of the present disclosures. Indeed, the novel methods, apparatusesand systems described herein can be embodied in a variety of otherforms; furthermore, various omissions, substitutions and changes in theform of the methods, apparatuses and systems described herein can bemade without departing from the spirit of the present disclosures. Theaccompanying claims and their equivalents are intended to cover suchforms or modifications as would fall within the scope and spirit of thepresent disclosures.

1. A system for reducing pulmonary inflammation and/or increasingbronchial compliance using transcutaneous stimulation of neuralstructures in a region of an ear of a patient, the system comprising: anauricular stimulation device comprising an in-ear component comprising afirst electrode, wherein the in-ear component is shaped for retention inone or more structures of the ear including the cavum of the ear, andthe first electrode is disposed on a surface of the in-ear component fornon-piercing contact with tissue proximate to vagal related neuralstructures, an earpiece component comprising a second electrode, whereinthe earpiece component is shaped for placement around an auricle of thepatient, the earpiece component is in electrical communication with thein-ear component, and the second electrode is disposed on a surface ofthe earpiece component for non-piercing contact with tissue proximate toa neural structure related to the auriculotemporal nerve; and a pulsegenerator in electrical communication with the earpiece component via aconnector, wherein the pulse generator is configured to control deliveryof transcutaneous stimulation therapy via the auricular stimulationdevice for reducing pulmonary inflammation and/or increasing bronchialcompliance, the therapy comprising delivering a first series ofstimulation pulses to the second electrode of the earpiece component forstimulating at least one of the auriculotemporal nerve, the lesseroccipital nerve, and the great auricular nerve, and delivering a secondseries of stimulation pulses to the first electrode of the in-earcomponent for stimulating the vagal related neural structures.
 2. Thesystem of claim 1, wherein: the first series of stimulation pulses isdelivered at a high frequency; and the second series of stimulationpulses is delivered at a low frequency.
 3. The system of claim 1,wherein: the first series of stimulation pulses is delivered at a low tomidrange frequency; and the second series of stimulation pulses isdelivered at a low to midrange frequency.
 4. The system of claim 1,wherein: the first series of stimulation pulses is delivered at a low tomidrange frequency; and the second series of stimulation pulses isdelivered at a midrange to high frequency.
 5. The system of claim 1,wherein: the first series of stimulation pulses is delivered at amidrange to high frequency; and the second series of stimulation pulsesis delivered at a low to mid-range frequency.
 6. The system of claim 1,wherein: the first series of stimulation pulses is delivered at amidrange to high frequency; and the second series of stimulation pulsesis delivered at a midrange to high frequency.
 7. The system of claim 1,wherein the pulse generator is configured to adjust delivery of thetranscutaneous stimulation therapy automatically responsive to i)feedback and/or ii) one or more control signals, wherein the one or morecontrol signals are provided by a) a separate computing device incommunication with the pulse generator, or b) via a user interface ofthe pulse generator.
 8. The system of claim 7, wherein delivery of thetranscutaneous stimulation therapy is adjusted according to thefeedback, wherein: the feedback is received by the pulse generator orthe separate computing device; and the feedback is in the form ofmonitoring at least one of EKG, EEG, or blood pressure to detect changesin one or more symptoms related to the bronchial inflammation.
 9. Thesystem of claim 1, wherein the pulmonary inflammation is caused by aviral or bacterial infection.
 10. The system of claim 9, wherein theviral infection is COVID-19.
 11. The system of claim 9, wherein theviral infection is severe acute respiratory syndrome (SARS).
 12. Thesystem of claim 9, wherein the viral infection is Middle Eastrespiratory syndrome coronavirus (MERS).
 13. The system of claim 1,wherein the pulmonary inflammation is chronic obstructive pulmonarydisease (COPD).
 14. The system of claim 1, wherein the in-ear componentis frictionally retained in the one or more structures of the ear. 15.The system of claim 1, wherein the earpiece component is adhesivelyretained around the auricle.
 16. A system for reducing pulmonaryinflammation and/or increasing bronchial compliance using transcutaneousstimulation of neural structures in a region of an ear of a patient, thesystem comprising: an auricular stimulation device comprising an in-earcomponent comprising a first electrode, wherein the first electrode isdisposed on a surface of the in-ear component for non-piercing contactwith tissue proximate to a first set of one or more neural structures inat least one of a concha, cavum, or tragus region of the ear, and anearpiece component comprising a second electrode, wherein the earpiececomponent is shaped for placement around an auricle of the patient, theearpiece component is in electrical communication with the in-earcomponent, and the second electrode is disposed on a surface of theearpiece component for non-piercing contact with tissue proximate to asecond set of one or more neural structures; and a pulse generator inelectrical communication with the earpiece component via a connector,wherein the pulse generator is configured to control delivery oftranscutaneous stimulation therapy via the auricular stimulation devicefor reducing pulmonary inflammation and/or increasing bronchialcompliance, the therapy comprising delivering a first series ofstimulation pulses to the first electrode of the in-ear component forstimulating the first set of one or more neural structures, anddelivering a second series of stimulation pulses to the second electrodeof the earpiece component for stimulating the second set of one or moreneural structures.
 17. The system of claim 16, wherein one of the firstseries or the second series of stimulation pulses is configured toreduce pulmonary inflammation and the other of the first series or thesecond series of stimulation pulses is configured to increase bronchialcompliance.
 18. The system of claim 16, wherein: the first set of one ormore neural structures includes at least a branch of the vagal nerve;and the second set of one or more neural structures includes at least abranch of one of the auriculotemporal nerve, the lesser occipital nerve,and the great auricular nerve.
 19. The system of claim 16, wherein thepulse generator is configured to synchronize delivery of the firstseries of stimulation pulses with delivery of the second series ofstimulation pulses.
 20. The system of claim 16, wherein reducingpulmonary inflammation comprises decreasing pro-inflammatory processesin the lungs.